Fick Robert J, Kroner Grace M, Nepal Binod, Magnani Roberta, Horowitz Scott, Houtz Robert L, Scheiner Steve, Trievel Raymond C
Department of Chemistry and Biochemistry, Utah State University , Logan, Utah 84322, United States.
Department of Horticulture, University of Kentucky , Lexington, Kentucky 40546, United States.
ACS Chem Biol. 2016 Mar 18;11(3):748-54. doi: 10.1021/acschembio.5b00852. Epub 2016 Jan 12.
Recent studies have demonstrated that carbon-oxygen (CH···O) hydrogen bonds have important roles in S-adenosylmethionine (AdoMet) recognition and catalysis in methyltransferases. Here, we investigate noncovalent interactions that occur between the AdoMet sulfur cation and oxygen atoms in methyltransferase active sites. These interactions represent sulfur-oxygen (S···O) chalcogen bonds in which the oxygen atom donates a lone pair of electrons to the σ antibonding orbital of the AdoMet sulfur atom. Structural, biochemical, and computational analyses of an asparagine mutation in the lysine methyltransferase SET7/9 that abolishes AdoMet S···O chalcogen bonding reveal that this interaction enhances substrate binding affinity relative to the product S-adenosylhomocysteine. Corroborative quantum mechanical calculations demonstrate that sulfonium systems form strong S···O chalcogen bonds relative to their neutral thioether counterparts. An inspection of high-resolution crystal structures reveals the presence of AdoMet S···O chalcogen bonding in different classes of methyltransferases, illustrating that these interactions are not limited to SET domain methyltransferases. Together, these results demonstrate that S···O chalcogen bonds contribute to AdoMet recognition and can enable methyltransferases to distinguish between substrate and product.
最近的研究表明，碳 - 氧（CH···O）氢键在甲基转移酶中S - 腺苷甲硫氨酸（AdoMet）的识别和催化过程中发挥着重要作用。在此，我们研究了甲基转移酶活性位点中AdoMet硫阳离子与氧原子之间发生的非共价相互作用。这些相互作用代表硫 - 氧（S···O）硫属元素键，其中氧原子将一对孤对电子捐赠给AdoMet硫原子的σ反键轨道。对赖氨酸甲基转移酶SET7/9中一个消除AdoMet S···O硫属元素键的天冬酰胺突变进行结构、生化和计算分析表明，相对于产物S - 腺苷高半胱氨酸，这种相互作用增强了底物结合亲和力。确证性的量子力学计算表明，锍系统相对于其中性硫醚对应物形成强的S···O硫属元素键。对高分辨率晶体结构的检查揭示了不同类别的甲基转移酶中存在AdoMet S···O硫属元素键，说明这些相互作用不仅限于SET结构域甲基转移酶。总之，这些结果表明S···O硫属元素键有助于AdoMet的识别，并能使甲基转移酶区分底物和产物。
